Table I . Per Cent Recovery of lsosorbide Dinitrate in Synthetic Mixtures (Drug plus Excipients) Sample IR Colorimetric No. method method 1 99.9 97.1 2 98.6 97.1 3 98.9 99.4 4 99.2 98.0 5 101.2 98.7 6 99.4 101.3 Mean 99.5 98.6 Std dev hO.9 h1.6
Table I t . Per Cent Recovery of lsosorbide Dinitrate in Tablet Preparations I R method Colorimetric method
gardless of the amount of base-line drift, the absorbance will remain the same when the A.4 method is applied. With the infrared method reported here, a determination can be made for concentrations of 0.12 mg/ml to 0.32 mg/ml in the sample solution. Lower or higher concentration samples may be analyzed with some decrease in precision. Excipients present in the tablets analyzed have been shown experimentally to exhibit no interference in the 1900-1600 cm-1 region. While commercial tablets may contain other excipients, it is unlikely that these will be present in quantities sufficient to cause appreciable interference.
This method is applicable to most organic nitrates, as long as such organic nitrates are soluble in a suitable solvent capable of yielding appropriate absorbance readings, and where there are no other interfering groups present in the molecule such as COOH, ketone. =, C=N. and amide. The method is quite precise and is suitable for routine laboratory analysis.
Sample
Commercial preparation Laboratory preparation
5
10
5
10
No
mg/tab
mgltab
mg tab
mg/tab
1 2 3 4 1 2 3 4
100.1 98.4 100.2 99.5 100.8 99.9 98.2 98.3
98.8 100.7 100.1 99.6 99.2 98.7 99.0 100.7
006 99 1 01 7 988 98 7 986 97 5 980
986 98 8 1003 101 0 99 3 973 98 1 976
Received for review February 15, 1973. Accepted May 2, 1973. Presented a t the 19th Canadian Spectroscopy Symposium and Exhibition. October 23-25, 1972, Le Chateau Champlain Hotel, Montreal, Quebec, Canada.
New Nuclear Magnetic Resonance Shift Reagents Roger E. Rondeau Air Force Materials Laboratory. A FMLILPH. Wright-PattersonAFB. Ohio 45433
Robert E. Sievers
Aerospace Research Laboratories A R L I L J . Wright-PattersonAFB, Ohio 45433 Since Hinckley reported the potential of rare earth chelates as S M R shift reagents in 1969 ( I ) , there has been a proliferation of papers describing successful applications of lanthanide shift reagents (LSR) to an ever-widening range of structural problems ( 2 ) . A recent survey by Horrocks ( 3 ) treated several Ln(thd), reagents [Ln(thd)3 = tris(2,2,6,6-tetramethyl-3,5-heptanedionato)lanthanide (In)], some of which cause still greater shifts than the popular Eu and Pr chelates. The work described here increases the variety of useful lanthanide shift reagents by examining a number of other extremely soluble Ln(fod)3 compounds [Ln(fod)3 = tris( 1,1,1,2,2,3,3-heptafluoro7,7-dimethyl-4,6-octanedionato)lanthanide(III)]. Fur thermore, the present study shows Eu(fod)s to be the most useful shift reagent for the detection and measurement of structural isomers of azoxybenzene derivatives. This work represents another step toward the goal of tailor-making shift reagents for special problems and provides information that will help in the selection of the Hinckley. J. Amer. Chem. SOC., 91. 5160 (1969). (2) R . E. Sievers, E d . , "NMR Shift Reagents," Academic Press, New Y o r k , N.Y.. 1973. ( 3 ) W. Dew. Horrocks and J. P. Sipe, d. Amer. Chem. SOC.,93, 6800 (1971). ( 1 ) C. C.
best shift reagent for a specific objective from the many shift reagents that are now available. In the first part of the study, furan and tetrahydrofuran (THF) were used to test the shifting abilities of nine trivalent lanthanide tris fod chelates: Eu, Yb. T m , Nd, Sm, Pr, Dy, Er, and Ho. Furan is a representative weak base which was used primarily to test the ability of these new reagents to interact with an extremely weak donor; none of the observed shifts was very large. On the other hand, with T H F all of the shift reagents induced appreciably large shifts in the spectra, and this substrate provided a more suitable basis for comparison.
EXPERIMENTAL Spectra were obtained a t 60 MHz with a Varian HAGO-IL spectrometer locked on t h e signal from -2% tetramethylsilane. T h e T H F used was refluxed over LiAlH4 for 18 hours a n d fractionally distilled. T h e solvent, CC14, was dried over Linde 4A molecular sieves. Sample solutions were prepared by Lawrence Knaak with 0.1 mmole of substrate in 0.5 ml CC14. T h e Ln(fod)a chelates were prepared according to Springer, Meek, and Sievers 14) and kept . are commercially available dry by desiccation over P z O ~ They from Eastman Kodak, Rochester, N.Y., and Willow Brook Laboratories, Waukesha, Wis. ( 4 ) C. S. Springer, D. W. Meek. and R E. Sievers, Inorg. Chem.. 6, 1105 (1967)
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Table I. Comparison of the Magnitude of Shift in the NMR Spectra of Tetrahydrofuran Induced by Various fod Chelatesa D
C
Upfield shift reagents H o ( f 0 d ) 3‘ Pr ( f o d ) Nd ( f o d ) 3 Sm(fod)
DY( f 0 d ) 3 ~
6 (pprn) for CHz adjacent to oxygenb
6 (ppm) for CH2 remote from oxygen
18.0 5.00
8.6 2.25 1 .oo 0.17 0.15
2.67
0.42 0.33
Ratio
0.48 0.45 0.37
0.40 0.45
Downfield shift reagents -18.2 -8.2 0.45 -7.08 -3.42 0.48 -3.08 1.20 0.39 -0.97 -0.40 0.41 mole THF and O W 5 mole of fod a Spectra obtained at 0 MHz chelaie dissolved in 0.5 ml CCI4. Because the mole ratio is so low, much larger shifts can be induced in practice by the addition of larger amounts of the fod chelates. Negative numbers refer to downfield shifts (ppm). Appreciable broadening with obliteration of fine structure. Because of excessive broadening a LSR/THF mole ratio of 0.01 was used. e Same as d but moie ratio of 0.001 was used.
Tm ( f 0 d ) 3 ~
Yb(f0d)s ELI(~o~)~ E r ( f ~ d ) ~ ~
I
I
5.0
4.0
PPM
I
I
3.0
2.0
Figure 1. 6 0 M H z N M R spectra of tRe methoxy methyl a n d benzyl methylene resonances of the isomeric mixture 4(4’)-methoxy-4’(4)-butylazoxybenzene (0.1 mmole in 0.5 mi CCI4)
+
(A) Diamagnetic substrate only: (B) A f 10 mg E ~ ( f o d ) (~C:) A 10 mg Y b ( f ~ d ) (D) ~; A 10 mg Eu(thd)3. Induced separation with Tm(fod)3 was 16 Hz in the methoxy methyls with slight broadening
+
I
/I
-
always be valid. Ho(fod)s and Tm(fod)s produced large shifts of the a-CHz resonance (18 ppm for a LSR/THF mole ratio of 0.1). In fact, the addition of only 1 mg of the Ho chelate caused an upfield shift of 100 Hz. This is one of the largest reported shifts of a vicinal proton. As in the case of the Ln(thd), chelates, the greater the shift, the greater the resulting dipolar broadening (3).The use of Ho(fod)s will therefore be limited to substrates for which considerable broadening can be tolerated. The efficiency of the fod chelates in separating resonance peaks of isomeric mixtures of unsymmetrically para-substituted azoxybenzenes is illustrated in Figures 1 and 2 . In each instance. 10 mg of the appropriate chelate was added. Since the molecular weights of all the fod chelates are nearly the same, the solutions are approximately equimolar. Consequently, the shifts induced can be taken as a rough indication of the relative efficiencies with which the spectrum of this substrate is altered. More rigorous quantitative comparisons are of little value because the relative efficiencies are not the same for all substrates. Figure 1 is a series of spectra showing the methoxy methyl and benzyl methylene resonances of the mixture of 4 and 4’-n-butyl-4’ and 4-methoxyazoxybenzenes. Resonance peaks of these isomers were first separated with Eu(fod)3, which caused bidirectional shifts because of the angular term in the expression for the pseudocontact interaction (5).
PI = K (3 cos201- l ) / r 1 3 I
I
I
4.0
5.0
3.0
I
2.0
PPM
Figure 2. 6 0 M H z N M R spectra of the methoxy methyl and benzyl methylene resonances of the isomeric mixture 4(4’)-methoxy-4’(4)-butyl-azoxybenzene (0.1 mmole in 0.5 ml CC14)
+
+
( A ) Diamagnetic substrate only: (B) A 10 mg Nd(fod)3: (C) A 10 10 mg H ~ ( f o d ) No ~ . induced separation with mg Pr(fod)3; (‘D) A Sm (fod)3
+
RESULTS AND DISCUSSION Table I shows the results of a comparative study of the shifting ability of various fod chelates when used to alter the spectrum of THF. I t should be kept in mind that comparative data of this type are highly dependent on the particular substrate, so extrapolations to other systems may not 2146
(1)
where K is a constant, rl is the distance vector from the rare earth metal to the proton i, and O1 is the angle between this vector and the principal magnetic axis. At values of the angle 8, greater than 34.7”, the (3 cos201 - 1) term becomes negative; this accounts for the upfield shift of the methoxy protons in the one isomer (6). In view of the much greater shifting power of several other fod chelates and because substantial broadening can be tolerated in monitoring the shifts of the methoxy methyl singlet. the performance of the various shift reagents was assessed for this particular application. Two conclusions can be (5) H. M. McConneil and R. E. Robertson, J . Chem. Phys., 29, 1361 (1958). (6) R. E. Rondeau. M . A. Berwick. M . P. Serve, and R. N. Steppel, J. Arner. Chem. SOC.. 94, 1096 (1972).
A N A L Y T I C A L C H E M I S T R Y , VOL. 45, NO. 1 2 , OCTOBER 1973
drawn from these data. First, Eu(fod)s is by far the most Yb(II1) may mean that the number of different possible suitable LSR for this particular set of isomers despite the conformations is reduced in the more compact ligand fact that other shift reagents exhibit u p to seven times the shell. With multifunctional substrates, it may be necessary to induced shift with THF. Second, Eu(thd)s does not cause any shifting, despite the presence of the same rare earth reverse the strategy and look for less stable complexes in metal and the well known success of this shift reagent hopes of reducing the likelihood of complex formation a t when used with other substrates. Presumably this is due more than one functional site on the substrate. This may also be minimized by utilizing high ratios of substrate to to the poorer Lewis acidity of the thd complexes relative to those with fod (7) which contain electron-withdrawing shift reagent, in which event it may be necessary conperfluoropropyl groups. versely to select a chelate that forms rather stable comNo one chelate will be the best choice for all applicaplexes, e . g . , Yb(fod)s, in order to produce observable tions. With an increasingly large number of choices of shifts. Success will undoubtedly be dependent on just how shift reagent, perhaps some empirical guidelines to assist different the nucleophilicities of the different sites on the in selection will be useful. For the first try a t spectral substrate are. If the sites are far enough removed in the clarification, E u ( f ~ d )is~ usually the best shift reagent structure, it may not be too great a problem to have overall. It forms more stable LSR-substrate complexes bound lanthanide a t both donors for some applications than Eu(thd)3, and it is consequently useful with a much such as spectral clarification, but this is disastrous if inbroader range of weak nucleophiles than any of the thd formation about conformations is desired. chelates. Some other chelates produce greater shifts, but For pragmatic reasons, the downfield shift reagents with considerably more peak broadening. In some inhave been the most widely used, but if upfield shifts are stances, it may be most advantageous to use Ho(fod)s if it desired, the best general-use reagent available appears to is not important to resolve fine structure. This could be be Pr(fod)3. Sm(fod)3 and Nd(fod)s are not as effective, important when very weak nucleophiles are being studied. and Ho(fod)3, while giving much larger shifts, does so only with loss of fine structure.-Broadening is very severe with Another way to overcome the problem of handling weak nucleophiles is to select chelates that form more stable Er(fod)s and Dy(fod)3. I t should be emphasized that in going from one shift recoordinate bonds. We have established in independent gas agent to another, differences are sometimes seen not only chromatographic studies ( 2 , 8-10) that the stability of the associated complex increases as the ionic radius of the metal in the magnitude of the shift and broadening but also in ion decreases because of the lanthanide contraction. the relative positions of the peaks. Consequently, if the patterns are still too complicated in a particular spectral Sometimes oligomerization complicates this generalization. As a rule, however, Yb(fod)3 is expected to form conregion with one shift reagent, additional information can siderably more stable complexes than Eu(fod)3. Peak possibly be obtained by trying a different shift reagent. broadening is not appreciably greater than with E ~ ( f o d ) ~ ,Thus, it appears that the precise shapes of the coordinaso the Yb complex may be a good choice for extremely tion site on the chelates and their symmetry may affect weak nucleophiles. Furthermore, the smaller size of not only the stability of the complex formed but also the orientation of the substrate relative to all the other (7) R. E. Rondeau and R. E. Sievers, J . Arner. Chem. SOC., 93, 1522 (1971). moieties in the ligand shell. (8) B. Feibush. M . F. Richardson, R. E. Sievers, and C. S . Springer, Jr., J. Amer. Chem. SOC., 94, 6717 (1972). (9) L. Froebe, J . J. Brooks, R . E . Sievers, and D. S . Dyer, Proc. int. Conf. Coord. Chem., Toronto, June 1972. (10) J. J. Brooks and R. E. Sievers, J. Chromatog. Sci., 11, 303 (1973).
Received for review July 28, 1972. Accepted April 16, 1973.
A N A L Y T I C A L C H E M I S T R Y , VOL. 45, N O . 12, OCTOBER 1973
2147
